Natriuretic peptides as predictors for atrial fibrillation recurrence after catheter ablation: A meta-analysis

Background: Catheter ablation (CA) has become the first-line treatment strategy for atrial fibrillation (AF) but remains with a substantial recurrence rate. The aim of this meta-analysis was to determine the association between baseline natriuretic peptide levels and AF recurrence after CA. Methods: We systematically searched PubMed, EMBASE, Web of Science, and Wiley-Cochrane Library for relevant studies published up until May 2022. Overall effect analysis and subgroup analysis were performed with Review Manager software. Results: Finally, 61 studies that met the inclusion criteria were included in our meta-analysis. Compared with the nonrecurrence group, the recurrence group had increased baseline level of atrial natriuretic peptide (ANP) (standardized mean difference [SMD] = 0.39, 95% confidence interval [CI]: 0.21–0.56), brain natriuretic peptide (BNP) (SMD = 0.51, 95% CI: 0.31–0.71), N-terminal pro-BNP (SMD = 0.71, 95% CI: 0.49–0.92), and midregional N-terminal pro-ANP (SMD = 0.91, 95% CI: 0.27–1.56). Conclusions: Increased baseline natriuretic peptide levels, including ANP, BNP, N-terminal pro-BNP, and midregional N-terminal pro-ANP, are associated with a higher risk of AF recurrence after CA. Nonetheless, further studies are needed to elucidate the predictive value of baseline natriuretic peptides in AF patients undergoing CA.


Introduction
Atrial fibrillation (AF) is a common cardiac rhythm disturbance associated with serious complications including strokes, thromboembolism, and cognitive impairments that can influence patients' quality of life and impose higher medical care costs. [1] The disease remains an increasing public health concern throughout the world. Approximately 3.9 million individuals aged over 60 years suffer from AF in China. [2] As a progressive disease, AF is associated with a higher risk of all-cause and cardiovascular death. [3] Nowadays, catheter ablation (CA) is recommended as the first-line treatment strategy for rhythm control due to its effectiveness in sustaining sinus rhythm. [4,5] However, it still has a substantial recurrence rate, and the success rate ranges from 30 to 85%. [6] Therefore, how to judge the prognosis of CA is particularly important.
Natriuretic peptides are primarily secreted by myocytes under various stimuli and have been widely used as important diagnostic and monitoring tools for cardiovascular diseases. [7] Meanwhile, studies have shown that AF patients have higher plasma natriuretic peptide concentrations than that in the control group, and the elevated natriuretic peptide levels decrease after CA restores sinus rhythm. [8,9] However, whether increased natriuretic peptide is a true predictor of AF recurrence still remains controversial. Therefore, we conducted this meta-analysis to include more studies, discover different kinds of natriuretic peptides, and identify the association between baseline natriuretic peptide levels and AF recurrence after CA.

Search strategy
In order to aggregate all of the relevant published studies, Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for all peer-reviewed studies. Medicine We searched PubMed, EMBASE, Web of Science, and Wiley-Cochrane Library for relevant studies published up until May 2022. The following search items were used: natriuretic peptide, AF, CA, and recurrence. The "related article" function was also used during the search; the references for retrieved articles were manually searched to avoid initial misses.

Selection criteria
The included studies had to fulfill the following inclusion criteria: studies were designed as randomized controlled trials, prospective observational studies, or retrospective observational studies; the study enrolled patients who underwent their first CA; post-ablation AF recurrence was assessed as an outcome; atrial arrhythmia including AF, atrial flutter, or atrial tachycardia confirmed by 12-lead electrocardiography or Holter electrocardiography is used in the assessment of AF recurrence; and the number of patients, mean (standard deviation [SD]) or median (range or interquartile range) level of natriuretic peptides within recurrence and nonrecurrence groups were provided.
The exclusion criteria were: non-human study; abstracts, reviews, unpublished reports, overlapped publications, non-English language articles; and AF patients underwent rate control strategies or surgical ablation.

Data extraction
Two reviewers independently extracted data, including publication information (first author name, publication year, and geographic region), study design, characteristics of participants (total number, mean age, gender proportions, AF and ablation type), follow-up duration, recurrence rates, and pre-ablation natriuretic peptide level of recurrence and nonrecurrence groups. Disagreement data were resolved by consensus or adjudication by a third author.

Quality assessment
The Newcastle-Ottawa Scale [10] was used to evaluate the quality of each study. It allocates 0 or 1 point to each numbered item in each category with the exception of comparability where up to 2 points can be assigned. The assessments were done independently by 2 authors. Any disagreements encountered were resolved by discussion. When no consensus could be achieved, a third reviewer was consulted for reconciliation.

Statistical analysis
Standardized mean difference (SMD) was used to present the pooled effect with a 95% confidence interval (CI). The SMD is an estimate of the effect size and can be interpreted as the difference between means of groups divided by the pooled SD. For baseline characteristics represented by median and range/IQR, mean and SD values were estimated using the method described by Luo et al [11] and McGrath et al. [12] Heterogeneity was assessed using the Cochrane Q test and I 2 index. When the heterogeneity test was P ≥ .05, or I 2 < 50% indicating low statistical heterogeneity, a fixed effect model was used; otherwise, a random effect model was chosen. The source of heterogeneity was analyzed using subgroup analysis. Sensitivity analysis was evaluated by determining whether the remaining results would be markedly affected after removing the relatively low-quality study. Overall effect analysis and subgroup analysis were performed with Review Manager software (RevMan Version 5.4.1, The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). Publication bias was appraised by visual inspection of funnel plots and Egger test conducted by Stata 15 (Stata Corp., College Station, TX). A trim-and-fill analysis was applied to investigate the potential influence of publication bias. P < .05 was considered statistically significant.

Ethics statement
An ethics statement is not applicable because this study is based exclusively on published literature. This study protocol conforms to the provisions of the Helsinki Declaration as revised in 2013.

Description of included studies
One thousand three hundred eighty-five studies were acquired after a primary search, and then 851 duplicates were excluded. Three hundred twenty-seven studies underwent the first sift-prescreening by scanning the title and abstracts, among which 221 were excluded. The remaining 106 studies were retrieved for the second selection, and the full texts were read and evaluated carefully. The flow diagram of studies screening was listed in Figure 1. Finally, 61 studies that met the inclusion criteria were included in our meta-analysis. Among them, 8 studies evaluated the association between baseline atrial natriuretic peptide (ANP) levels and AF recurrence after CA, 37 studies evaluated for brain natriuretic peptide (BNP), 25 studies evaluated for N-terminal pro-BNP (NT-proBNP), and 4 studies evaluated for midregional N-terminal pro-ANP (MR-proANP). The demographic and clinical properties of eligible studies are presented in Table 1 and Supplementary Table S1, Supplemental Digital Content, http://links.lww.com/MD/I921. For quality assessment, all included studies were of relatively high quality with the Newcastle-Ottawa Scale scores ranging from 6 to 8 points.

Baseline ANP level and the post-ablation AF recurrence
After meta-analysis of 8 related studies, the pooled results indicated that there was a statistically significant association between baseline ANP level and post-ablation AF recurrence (SMD = 0.39, 95% CI: 0.21-0.56, P < .0001; Fig. 2). Heterogeneity testing showed that moderate heterogeneity existed with I 2 = 45% (P = .08). The heterogeneity was still present after subgroup analysis by follow-up duration, AF type, or sample size (Supplementary Figure S1, Supplemental Digital Content, http://links.lww.com/ MD/I922). Since these underlying confounding factors could not explain the heterogeneity, sensitivity analysis was performed by removing 2 relatively low-quality studies to evaluate the stability and reliability of our results. We found that the heterogeneity decreased significantly by excluding 2 relatively low-quality studies (I 2 = 0%), but the overall pooled effects did not change statistically (SMD = 0.23, 95% CI: 0.02-0.44, P = .03; Supplementary Figure S2, Supplemental Digital Content, http://links.lww.com/ MD/I923), suggesting the result reliable.

Baseline BNP level and the post-ablation AF recurrence
Based on the 37 related studies, our meta-analysis showed that the AF recurrence group had a significantly greater baseline BNP level than the nonrecurrence group, and the pooled SMD was 0.51 (95% CI: 0.31-0.71, P < .00001; Fig. 3). However, heterogeneity testing revealed a significant heterogeneity (I 2 = 93%). Moderate or high heterogeneity still existed after subgroup analysis by follow-up duration, AF type, sample size, or geographic region (Supplementary Figure S3

Baseline NT-proBNP level and the post-ablation AF recurrence
Significant association between pre-ablation baseline NT-proBNP level and post-ablation AF recurrence was found in our meta-analysis of 25 related studies. The pooled SMD was 0.71 (95% CI: 0.49-0.92, P < .00001, Fig. 4). Meanwhile, there was a remarkable heterogeneity among the studies with I 2 = 84% (P < .00001). After subgroup analysis by follow-up duration, AF type, sample size, or geographic region, moderate or high heterogeneity still existed (Supplementary Figure S5

Baseline MR-proANP level and the post-ablation AF recurrence
There were 4 studies that provided data about baseline MR-proANP levels. A statistically significant association was found between baseline MR-proANP level and post-ablation AF recurrence. The pooled SMD was 0.91 (95% CI: 0.27-1.56, P = .005, Fig. 5). Meanwhile, there was still a remarkable heterogeneity among the studies with I 2 = 88% (P < .0001). In sensitivity analysis, the result was not significantly altered after excluding the relatively low-quality study (SMD = 1.01, 95% CI: 0.23-1.79, P = .01; Supplementary Figure S7, Supplemental Digital Content, http://links.lww.com/MD/I928), demonstrating the results were stable.

Publication bias analysis
Publication bias analysis was performed when 10 or more studies were retrieved (BNP and NT-proBNP). The funnel plots of BNP were symmetrical with Egger test P = .079, revealing no publication bias was present (Supplementary Figure S8A,  Table 1 Characteristics of included studies.

Author
Year Region

Discussion
CA, mainly through PVI, is an effective treatment to restore sinus rhythm for patients with AF, [13] but the prognosis after therapy is complex, this includes recurrence or recurrence-free, short-term or long-term recurrence. Predictors for the prognosis are also miscellaneous. [8,14,15] Therefore, identifying and predicting highrisk patients with AF recurrence can help doctors to make an optimized patient selection, inform patients of the risk-benefit ratio, guide surgeons to select the best ablation strategy, and implement individualized treatment strategies. Natriuretic peptides refer to a class of cardiac neurohormones secreted from myocardium cells mostly in response to increased wall tension due to pressure or volume overload. [16] The value of natriuretic peptides as biomarkers useful for cardiovascular diseases was first described in patients with heart failure and continued in those with acute coronary syndrome presentations. [1] Over the past decade, there has also been growing evidence of the use of natriuretic peptides in AF. [17,18] Although the utilization of NPs in heart failure management has been well established, the importance of these biomarkers in relation to AF has not been fully clarified. Consequently, comprehensively analyzing the role of different kinds of natriuretic peptides in AF management may thus facilitate the integration of these widely available biomarkers in clinical applications. It is worth mentioning that this is one of the few articles to investigate the effect of different natriuretic peptides on the recurrence of AF after ablation with the widest variety of natriuretic peptides. This meta-analysis identified 61 observational NT-proBNP 8 AF = atrial fibrillation, ANP = atrial natriuretic peptide, BNP = brain natriuretic peptide, CB = cryoballoon, F = female, M = male, MR-proANP = midregional N-terminal pro-ANP, NA = not available, Nonparo = non-paroxysmal AF, NOS = Newcastle-Ottawa Scale, NT-proBNP = N-terminal pro-brain natriuretic peptide, Paro = paroxysmal AF, Pers = persistent AF, RF = radiofrequency. studies that investigated the potential association between baseline natriuretic peptides and AF recurrence after CA. The present results suggested that patients with AF recurrence have greater baseline ANP, BNP, NT-proBNP, and MR-proANP levels, indicating a predictive role for natriuretic peptides in the recurrence of AF after CA. ANP is primarily expressed and stored in the atrium and synthesized as pre-prohormones. The primary stimulus for ANP release is atrial wall stretch resulting from increased intravascular volume. [19] The plasma level of ANP in healthy individuals is approximately 20 pg/mL and is evaluated to be 10-to 100-fold higher in patients with heart failure. [20] Meanwhile, it is also well known that ANP is increased in the setting of atrial tachyarrhythmias, including AF, independent of the left atrium diameter. [17] The elevated concentration of ANP in the peripheral plasma obtained during persistent AF is considered to be caused by the loss of atrial contraction and the rapid ventricular rate, which leads to an increased central volume loading and atrial stretch. [21] In this meta-analysis, 8 studies were pooled and a significant association between baseline ANP level and post-ablation AF recurrence was found. Previous meta-analysis had also revealed the same result. [6] BNP is minimally stored in granules in the ventricles and secreted directly in large bursts following stimulation. [22] The plasma level of BNP in healthy individuals is approximately 3.5 pg/mL and is evaluated to be 100-fold higher in patients with heart failure. [23] Atrial dysrhythmia would also increase BNP secretion. Asynchronous contraction of the atrial myocardium could produce a tethering effect of atrial myocardial fibers that may stimulate the secretion of BNP. [24] Our findings highlight a strong association between elevated BNP and AF recurrence following CA. Another important finding is that BNP levels were affected by follow-up time and region in the subgroup analysis. Patients with short follow-up time (≤3 months) within the cohorts reduced the strength of the association of BNP levels with ablation outcomes. Furthermore, the pooled results for the American region still show no significant association between them (SMD = 0.20, 95% CI: −0.21 to 0.61, P = .33), even though Shaikh et al [25] showed that  circulating BNP levels were independently associated with late AF recurrence after pulmonary vein isolation. NT-proBNP, coexisting in circulation with BNP in 1 to 1, is easy to be determined because of its longer half-life (3 to 4 times longer than BNP), higher quantity (16 to 20-fold higher than BNP), and more stable concentration in the blood, which makes NT-proBNP concentrations relatively more stable than BNP over brief time periods. [26] Thus, plasma NT-proBNP level as a cardiac biomarker may be an interesting alternative to BNP. [27] Based on 25 related studies, our meta-analysis shows that the AF recurrence group had a significantly higher pre-ablation level of NT-proBNP. In 2009, Hwang et al demonstrated that NT-proBNP levels were an independent predictor of AF recurrence in a group of patients with paroxysmal AF and persistent AF after multivariate analysis. [28] Besides, NT-proBNP may be a possible biomarker of the hormonal status subsequently reflecting the hormonal remodeling of the atria in patients with AF. [27] Meanwhile, some studies have failed to find a significant association between NT-proBNP and AF recurrence. Giannopolous et al performed a post hoc analysis of a prospective study of hypertensive patients with paroxysmal AF. Baseline NT-proBNP levels were higher in patients with recurrence than in those who remained arrhythmia-free, but the association was rendered non-significant when adjusted for variables. [29] MR-proANP is a stable peptide that results from the cleavage of proANP (pro-ANP) [30] and proANP is stored and released by atrial cardiomyocytes and is cleaved into mature ANP and its N-terminal fragment, NT-proANP. [31] Within this fragment is the midregional section, MR-proANP, which has a longer half-life than mature ANP, making its assessment more reliable. [32] It was previously shown that MR-proANP is elevated in numerous pathologies specifically affecting the left atrium, such as mitral stenosis. [30,33] Meanwhile, MR-proANP is increased in patients with AF, independently of hemodynamic conditions, and also that there is a link between AF burden and MR-proANP levels. [34] Other studies have also reported that CA for AF significantly reduced plasma concentrations of ANP and MR-proANP in the long term. [35] In our meta-analysis, 4 studies were pooled and showed a statistically significant association between baseline MR-proANP level and post-ablation AF recurrence.
The explanation for the predictive role of natriuretic peptides in the recurrence of AF may be as follows: Firstly, it has been reported that elevated levels of natriuretic peptides are associated with an increase in left atrial size, which may increase the risk of recurrence of AF due to atrial fibrosis and remodeling after ablation. [36] Secondly, natriuretic peptide is recognized as a diagnostic marker of heart failure. The increase of natriuretic peptide levels before ablation may reflect cardiac dysfunction, which may cause AF through intracellular calcium overload, worsening myocardial fibrosis, decreased conduction velocity, and increased dispersity of the refractory period. [37]

Limitation
Undoubtedly, there were several potential limitations in this meta-analysis. First, the retrieved studies in our meta-analysis were observational studies rather than randomized control trials, in which comparability between groups was not easy to be controlled. Some of them had a relatively small sample size.  Second, Moderate or high heterogeneity existed among studies that were utilized for assessments. The contributing factors to heterogeneity include variation in follow-up time (from 3 to 63 months), sample size (from 26 to 1410), and AF type. Third, our inclusion criteria focused on studies in English, which led to selection or allocation biases, and affected the results of our meta-analysis. Fourth, we did not assess the prognostic value of baseline natriuretic peptides level by continuous variable due to insufficient such data. Finally, publication bias was found in the studies pooling NT-proBNP outcomes. However, the "trim-andfill" analysis indicated that the predictive value of NT-proBNP level had not changed obviously after adjustment of publication bias.

Conclusion
In conclusion, our meta-analysis indicated that increased baseline natriuretic peptide levels, including ANP, BNP, NT-proBNP, and MR-proANP, are associated with a higher risk of AF recurrence after CA. Measurement of these baseline levels should be recommended among AF patients before CA. Considering the limitations described above, further well-designed, larger, and long-term studies are needed to elucidate the predictive value of baseline natriuretic peptides in AF patients undergoing CA.